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PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma.
- Source :
-
Cancer research [Cancer Res] 2016 Aug 15; Vol. 76 (16), pp. 4708-19. Date of Electronic Publication: 2016 Jun 20. - Publication Year :
- 2016
-
Abstract
- Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila Cancer Res; 76(16); 4708-19. ©2016 AACR.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Animals
Astrocytes metabolism
Blotting, Western
Cell Proliferation
Drosophila
Glycolysis physiology
Heterografts
Humans
Immunohistochemistry
Mice
Mice, Inbred NOD
Mice, SCID
Oxidative Stress physiology
Brain Neoplasms pathology
Glioblastoma pathology
Protein Kinases metabolism
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 76
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 27325644
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-15-3079